PIGA mutations and glycosylphosphatidylinositol anchor dysregulation in polyposis-associated duodenal tumorigenesis.

The pathogenesis of duodenal tumours in the inherited tumour syndromes Familial Adenomatous Polyposis (FAP) and MUTYH-associated Polyposis (MAP) is poorly understood. This study aimed to identify genes that are significantly mutated in these tumours and to explore the effects of these mutations. Whole exome and whole transcriptome sequencing identified recurrent somatic coding variants of PIGA in 19/70 (27%) FAP and MAP duodenal adenomas, and further confirmed the established driver roles for APC and KRAS. PIGA catalyses the first step in glycosylphosphatidylinositol (GPI) anchor biosynthesis. Flow cytometry of PIGA-mutant adenoma-derived and CRISPR-edited duodenal organoids confirmed loss of GPI anchors in duodenal epithelial cells and transcriptional profiling of duodenal adenomas revealed transcriptional signatures associated with loss of PIGA. Implications: PIGA somatic mutation in duodenal tumours from patients with FAP and MAP and loss of membrane GPI-anchors may present new opportunities for understanding and intervention in duodenal tumorigenesis.

Action does not drive visual biases in peri-tool space.

Observers experience visual biases in the area around handheld tools. These biases may occur when active use leads an observer to incorporate a tool into the body schema. However, the visual salience of a handheld tool may instead create an attentional prioritization that is not reliant on body-based representations. We investigated these competing explanations of near-tool visual biases in two experiments during which participants performed a target detection task. Targets could appear near or far from a tool positioned next to a display. In Experiment 1, participants showed facilitation in detecting targets that appeared near a simple handheld rake tool regardless of whether they first used the rake to retrieve objects, but participants who only viewed the tool without holding it were no faster to detect targets appearing near the rake than targets that appeared on the opposite side of the display. In a second experiment, participants who held a novel magnetic tool again showed a near-tool bias even when they refrained from using the tool. Taken together, these results suggest active use is unnecessary, but visual salience is not sufficient, to introduce visual biases in peri-tool space.

Dominantly inherited micro-satellite instable cancer - the four Lynch syndromes - an EHTG, PLSD position statement.

The recognition of dominantly inherited micro-satellite instable (MSI) cancers caused by pathogenic variants in one of the four mismatch repair (MMR) genes MSH2, MLH1, MSH6 and PMS2 has modified our understanding of carcinogenesis. Inherited loss of function variants in each of these MMR genes cause four dominantly inherited cancer syndromes with different penetrance and expressivities: the four Lynch syndromes. No person has an "average sex "or a pathogenic variant in an "average Lynch syndrome gene" and results that are not stratified by gene and sex will be valid for no one. Carcinogenesis may be a linear process from increased cellular division to localized cancer to metastasis. In addition, in the Lynch syndromes (LS) we now recognize a dynamic balance between two stochastic processes: MSI producing abnormal cells, and the host's adaptive immune system's ability to remove them. The latter may explain why colonoscopy surveillance does not reduce the incidence of colorectal cancer in LS, while it may improve the prognosis. Most early onset colon, endometrial and ovarian cancers in LS are now cured and most cancer related deaths are after subsequent cancers in other organs. Aspirin reduces the incidence of colorectal and other cancers in LS. Immunotherapy increases the host immune system's capability to destroy MSI cancers. Colonoscopy surveillance, aspirin prevention and immunotherapy represent major steps forward in personalized precision medicine to prevent and cure inherited MSI cancer.

Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells.

Cellular DNA damage caused by reactive oxygen species is repaired by the base excision repair (BER) pathway which includes the DNA glycosylase MUTYH. Inherited biallelic MUTYH mutations cause predisposition to colorectal adenomas and carcinoma. However, the mechanistic progression from germline MUTYH mutations to MUTYH-Associated Polyposis (MAP) is incompletely understood. Here, we sequence normal tissue DNAs from 10 individuals with MAP. Somatic base substitution mutation rates in intestinal epithelial cells were elevated 2 to 4-fold in all individuals, except for one showing a 31-fold increase, and were also increased in other tissues. The increased mutation burdens were of multiple mutational signatures characterised by C > A changes. Different mutation rates and signatures between individuals are likely due to different MUTYH mutations or additional inherited mutations in other BER pathway genes. The elevated base substitution rate in normal cells likely accounts for the predisposition to neoplasia in MAP. Despite ubiquitously elevated mutation rates, individuals with MAP do not display overt evidence of premature ageing. Thus, accumulation of somatic mutations may not be sufficient to cause the global organismal functional decline of ageing.

Germline MBD4 deficiency causes a multi-tumor predisposition syndrome.

We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5'-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management.

A pre-registered, multi-lab non-replication of the action-sentence compatibility effect (ACE).

The Action-sentence Compatibility Effect (ACE) is a well-known demonstration of the role of motor activity in the comprehension of language. Participants are asked to make sensibility judgments on sentences by producing movements toward the body or away from the body. The ACE is the finding that movements are faster when the direction of the movement (e.g., toward) matches the direction of the action in the to-be-judged sentence (e.g., Art gave you the pen describes action toward you). We report on a pre-registered, multi-lab replication of one version of the ACE. The results show that none of the 18 labs involved in the study observed a reliable ACE, and that the meta-analytic estimate of the size of the ACE was essentially zero.

Aging and Inhibition of Return to Locations and Objects.

Inhibition of return (IOR) is thought to reflect a cognitive mechanism that biases attention from returning to previously engaged items. While models of cognitive aging have proposed deficits within select inhibitory domains, older adults have demonstrated preserved IOR functioning in previous studies. The present study investigated whether inhibition associated with objects shows the same age patterns as inhibition associated with locations. Young adults (18-22 years) and older adults (60-86 years) were tested in two experiments measuring location- and object-based IOR. Using a dynamic paradigm (Experiment 1), both age groups produced significant location-based IOR, but only young adults produced significant object-based IOR, consistent with previous findings. However, with a static paradigm (Experiment 2), young adults and older adults produced both location- and object-based IOR, indicating that object-based IOR is preserved in older adults under some conditions. The findings provide partial support for unique age-related inhibitory patterns associated with attention to objects and locations.

G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling.

Ras GTPase-activating protein-binding proteins 1 and 2 (G3BP1 and G3BP2, respectively) are widely recognized as core components of stress granules (SGs). We report that G3BPs reside at the cytoplasmic surface of lysosomes. They act in a non-redundant manner to anchor the tuberous sclerosis complex (TSC) protein complex to lysosomes and suppress activation of the metabolic master regulator mechanistic target of rapamycin complex 1 (mTORC1) by amino acids and insulin. Like the TSC complex, G3BP1 deficiency elicits phenotypes related to mTORC1 hyperactivity. In the context of tumors, low G3BP1 levels enhance mTORC1-driven breast cancer cell motility and correlate with adverse outcomes in patients. Furthermore, G3bp1 inhibition in zebrafish disturbs neuronal development and function, leading to white matter heterotopia and neuronal hyperactivity. Thus, G3BPs are not only core components of SGs but also a key element of lysosomal TSC-mTORC1 signaling.

Vision is biased near handheld, but not remotely operated, tools.

Previous studies have shown that after actively using a handheld tool for a period of time, participants show visual biases toward stimuli presented near the end of the tool. Research suggests this is driven by an incorporation of the tool into the observer's body schema, extending peripersonal space to surround the tool. This study aims to investigate whether the same visual biases might be seen near remotely operated tools. Participants used tools-a handheld rake (Experiment 1), a remote-controlled drone (Experiment 2), a remote-controlled excavator (Experiment 3), or a handheld excavator (Experiment 4)-to rake sand for several minutes, then performed a target-detection task in which they made speeded responses to targets appearing near and far from the tool. In Experiment 1, participants detected targets appearing near the rake significantly faster than targets appearing far from the rake, replicating previous findings. We failed to find strong evidence of improved target detection near remotely operated tools in Experiments 2 and 3, but found clear evidence of near-tool facilitation in Experiment 4 when participants physically picked up the excavator and used it as a handheld tool. These results suggest that observers may not incorporate remotely operated tools into the body schema in the same manner as handheld tools. We discuss potential mechanisms that may drive these differences in embodiment between handheld and remote-controlled tools.

APC transcription studies and molecular diagnosis of familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) is characterised by the development of hundreds to thousands of colorectal adenomas and results from inherited or somatic mosaic variants in the APC gene. Index patients with suspected FAP are usually investigated by APC coding region sequence and dosage analysis in a clinical diagnostic setting. The identification of an APC variant which is predicted to alter protein function enables predictive genetic testing to guide the management of family members. This report describes a 4-generation family with a phenotype consistent with FAP, but in which an APC variant had not been identified, despite testing. To explore this further, quantitative PCR (qPCR) was employed to assess APC transcription, demonstrating reduced levels of APC RNA. Next generation sequencing (NGS) identified the APC 5'UTR/ Exon 1 variant, c.-190 G>A, that had been reported previously in an another FAP family with APC allelic imbalance. Quantitative RNA studies and DNA sequencing of the APC promoters/ Exon 1 may be useful diagnostically for patients with suspected FAP when coding region variants cannot be identified.

Change detection for real-world objects in perihand space.

Recent evidence has demonstrated that observers experience visual-processing biases in perihand space that may be tied to the hands' relevance for grasping actions. Our previous work suggested that when the hands are positioned to afford a power-grasp action, observers show increased temporal sensitivity that could aid with fast and forceful action, whereas when the hands are instead at the ready to perform a precision-grasp action, observers show enhanced spatial sensitivity that benefits delicate and detail-oriented actions. In the present investigation we seek to extend these previous findings by examining how object affordances may interact with hand positioning to shape visual biases in perihand space. Across three experiments, we examined how long participants took to perform a change detection task on photos of real objects, while we manipulated hand position (near/far from display), grasp posture (power/precision), and change type (orientation/identity). Participants viewed objects that afforded either a power grasp or a precision grasp, or were ungraspable. Although we were unable to uncover evidence of altered vision in perihand space in our first experiment, mirroring previous findings, in Experiments 2 and 3 our participants showed grasp-dependent biases near the hands when detecting changes to target objects that afforded a power grasp. Interestingly, ungraspable target objects were not subject to the same perihand space biases. Taken together, our results suggest that the influence of hand position on change detection performance is mediated not only by the hands' grasp posture, but also by a target object's affordances for grasping.

The influence of stress on attentional bias to threat: An angry face and a noisy crowd.

During stress, attentional capture by threatening stimuli may be particularly adaptive. Individuals are more efficient at identifying threatening faces in a crowd than identifying nonthreatening faces (e.g., Öhman et al., Journal of Experimental Psychology: General, 130(3): 466-478, 2001a, Öhman et al., Journal of Personality and Social Psychology, 80(3): 381-396, 2001b). However, under conditions of stress, when attention to threat may be most critical, cognitive processes are generally disrupted. The present study explored the attentional advantage of threatening stimuli under stressful conditions. We exposed participants to either high or low stress conditions during a visual search task displaying threatening and nonthreatening facial targets among distractors. Participants' accuracy, reaction times, and self-reported stress were measured. Stress introduced a speed-accuracy trade-off: participants in the high-stress condition were faster, but less accurate, than participants in the low-stress condition. Although both groups of participants showed relative performance advantages in detecting threatening compared with nonthreatening stimuli, this advantage was markedly larger for participants in the high-stress condition. This suggests that the established stress-mediated increase in the activity of the ventral neural network responsible for the reorienting of attention may have enhanced the ability to detect threatening stimuli or buffered the disruptive effects of stress on this process. Our findings highlight the potentially adaptive nature of stress disruption on attentional processes and align research on the anger superiority effect and automated attentional processes under stress.

Secular changes in severity of intellectual disability in tuberous sclerosis complex: A reflection of improved identification and treatment of epileptic spasms?

Tuberous sclerosis complex (TSC) is a multisystem genetic disorder caused by mutations in TSC1 or TSC2. Epilepsy occurs in 80%-90% of affected individuals during their lifetime, and up to one-third of children with TSC will develop epileptic (infantile) spasms, for which vigabatrin has been shown to be particularly effective. Epilepsy severity and epileptic spasms are consistent markers of risk for the development of intellectual impairment in TSC. Although previous studies demonstrate a bimodal distribution of intellectual ability in TSC, recent findings suggest a unimodal distribution, which may reflect a change in IQ distribution over time. We compared 3 large historical UK cohorts of TSC (n = 331) that show varied distributions of intellectual ability, first ruling out differences in study methodology. Later-born individuals had a higher frequency of reported spasms and higher likelihood of vigabatrin administration, but were less likely to have profound intellectual impairment, compared to the earlier-born individuals. Our findings suggest that epileptic spasms went undetected in the older patients and therefore were not treated, leading to a higher occurrence of profound impairment, whereas the later born cohort had better access to treatment. These findings support the importance of early identification and treatment of seizures in TSC.

Immobilization does not disrupt near-hand attentional biases.

Observers show biases in attention when viewing objects within versus outside of their hands' grasping space. While the hands' proximity to stimuli plays a key role in these effects, recent evidence suggests an observer's affordances for grasping actions also shape visual processing near the hands. The current study examined the relative contributions of proximity and affordances in introducing attentional biases in peripersonal space. Participants placed a single hand on a visual display and detected targets appearing near or far from the hand. Across conditions, the hand was either free, creating an affordance for a grasping action, or immobilized using an orthosis, interfering with the potential to grasp. Replicating previous findings, participants detected targets appearing near the hand more quickly than targets appearing far from the hand. Immobilizing the hands did not disrupt this effect, suggesting that proximity alone is sufficient to facilitate target detection in peripersonal space.

The impact of chromoendoscopy for surveillance of the duodenum in patients with MUTYH-associated polyposis and familial adenomatous polyposis.

BACKGROUND AND AIMS: Duodenal polyposis and cancer have become a key issue for patients with familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). Almost all patients with FAP will develop duodenal adenomas, and 5% will develop cancer. The incidence of duodenal adenomas in MAP appears to be lower than in FAP, but the limited available data suggest a comparable increase in the relative risk and lifetime risk of duodenal cancer. Current surveillance recommendations, however, are the same for FAP and MAP, using the Spigelman score (incorporating polyp number, size, dysplasia, and histology) for risk stratification and determination of surveillance intervals. Previous studies have demonstrated a benefit of enhanced detection rates of adenomas by use of chromoendoscopy both in sporadic colorectal disease and in groups at high risk of colorectal cancer. We aimed to assess the effect of chromoendoscopy on duodenal adenoma detection, to determine the impact on Spigelman stage and to compare this in individuals with known pathogenic mutations in order to determine the difference in duodenal involvement between MAP and FAP. METHODS: A prospective study examined the impact of chromoendoscopy on the assessment of the duodenum in 51 consecutive patients with MAP and FAP in 2 academic centers in the United Kingdom (University Hospital Llandough, Cardiff, and St Mark's Hospital, London) from 2011 to 2014. RESULTS: Enhanced adenoma detection of 3 times the number of adenomas after chromoendoscopy was demonstrated in both MAP (P = .013) and FAP (P = .002), but did not affect adenoma size. In both conditions, there was a significant increase in Spigelman stage after chromoendoscopy compared with endoscopy without dye spray. Spigelman scores and overall adenoma detection was significantly lower in MAP compared with FAP. CONCLUSIONS: Chromoendoscopy improved the diagnostic yield of anomas in MAP and FAP 3-fold, and in both MAP and FAP this resulted in a clinically significant upstaging in Spigelman score. Further studies are required to determine the impact of improved adenoma detection on the management and outcome of duodenal polyposis.

Burden and Profile of Somatic Mutation in Duodenal Adenomas from Patients with Familial Adenomatous- and MUTYH-associated Polyposis.

Purpose: Duodenal polyposis and cancer are important causes of morbidity and mortality in familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). This study aimed to comprehensively characterize somatic genetic changes in FAP and MAP duodenal adenomas to better understand duodenal tumorigenesis in these disorders.Experimental Design: Sixty-nine adenomas were biopsied during endoscopy in 16 FAP and 10 MAP patients with duodenal polyposis. Ten FAP and 10 MAP adenomas and matched blood DNA samples were exome sequenced, 42 further adenomas underwent targeted sequencing, and 47 were studied by array comparative genomic hybridization. Findings in FAP and MAP duodenal adenomas were compared with each other and to the reported mutational landscape in FAP and MAP colorectal adenomas.Results: MAP duodenal adenomas had significantly more protein-changing somatic mutations (P = 0.018), truncating mutations (P = 0.006), and copy number variants (P = 0.005) than FAP duodenal adenomas, even though MAP patients had lower Spigelman stage duodenal polyposis. Fifteen genes were significantly recurrently mutated. Targeted sequencing of APC, KRAS, PTCHD2, and PLCL1 identified further mutations in each of these genes in additional duodenal adenomas. In contrast to MAP and FAP colorectal adenomas, neither exome nor targeted sequencing identified WTX mutations (P = 0.0017).Conclusions: The mutational landscapes in FAP and MAP duodenal adenomas overlapped with, but had significant differences to those reported in colorectal adenomas. The significantly higher burden of somatic mutations in MAP than FAP duodenal adenomas despite lower Spigelman stage disease could increase cancer risk in the context of apparently less severe benign disease. Clin Cancer Res; 23(21); 6721-32. ©2017 AACR.

Action Experience Drives Visual-Processing Biases Near the Hands.

Observers experience affordance-specific biases in visual processing for objects within the hands' grasping space, but the mechanism that tunes visual cognition to facilitate action remains unknown. I investigated the hypothesis that altered vision near the hands is a result of experience-driven plasticity. Participants performed motion-detection and form-perception tasks-while their hands were either near the display, in atypical grasping postures, or positioned in their laps-both before and after learning novel grasp affordances. Participants showed enhanced temporal sensitivity for stimuli viewed near the backs of the hands after training to execute a power grasp using the backs of their hands (Experiment 1), but showed enhanced spatial sensitivity for stimuli viewed near the tips of their little fingers after training to use their little fingers to execute a precision grasp (Experiment 2). These results show that visual biases near the hands are plastic, facilitating processing of information relevant to learned grasp affordances.

Visual processing is biased in peripersonal foot space.

Objects in peripersonal space are of great importance for interaction with the sensory world. A variety of research exploring sensory processing in peripersonal space has produced extensive evidence for altered vision near the hands. However, visual representations of the peripersonal space surrounding the feet remain unexplored. In a set of four experiments, we investigated whether observers experience biases in visual processing for objects near the feet that mirror the alterations associated with near-hand space. Participants performed attentional-cueing tasks in which they detected targets appearing (1) near or far from a single visible foot, (2) near one of two visible feet, (3) near or far from a nonfoot visual anchor, or (4) near or far from an occluded foot. We found a temporal cost associated with detecting targets appearing far from a visible foot, but no biases were associated with targets appearing near versus far from either a nonfoot visual anchor or an occluded foot. These results provide the first evidence suggesting that objects within stepping or kicking distance are processed differently from objects outside of peripersonal foot space.

Inherited predisposition to colorectal cancer: towards a more complete picture.

Colorectal carcinoma (CRC) is the third most common cancer worldwide. Hereditary factors are important in 15%-35% of affected patients. This review provides an update on the genetic basis of inherited predisposition to CRC. Currently known genetic factors include a group of highly penetrant mutant genes associated with rare mendelian cancer syndromes and a group of common low-penetrance alleles that have been identified through genetic association studies. Additional mechanisms, which may underlie a predisposition to CRC, will be outlined, for example, variants in intermediate penetrance alleles. Recent findings, including mutations in POLE, POLD1 and NTHL1, will be highlighted, and we identify gaps in present knowledge and consider how these may be addressed through current and emerging genomic approaches. It is expected that identification of the missing heritable component of CRC will be resolved through evermore comprehensive cataloguing and phenotypic annotation of CRC-associated variants identified through sequencing approaches. This will have important clinical implications, particularly in areas such as risk stratification, public health and CRC prevention.